Inflammatory diseases are a large family of disorders in which the activity of elements of the immune system cause a wide range of signs and symptoms in the body including fever, rash, pain, swelling, weakness and many types of tissue damage. A subset of inflammatory diseases are also classified as autoimmune diseases because of evidence that in these cases the activation of the immune system is linked to an aberrant reactivity against some of the body's own normal proteins or other structures. Autoimmune inflammatory diseases can result in symptoms that range from moderate to severe such as blindness, being wheelchair bound or bedridden, or even to death. Variability in disease presentation is common and severity can vary markedly between patients with the same disorder.
NMO is a rare autoimmune inflammatory disorder with prevalence estimated as 1.5-4.4 per 100,000 of the population resulting in a calculated 12,000-35,000 patients in the US and Europe combined. The age of onset can vary from adolescence or even childhood, to late adulthood with a median of late 30's. There is a marked female to male preponderance reported to be as high as 9:1.
Clinical onset of NMO is usually acute and in two thirds of cases a prodrome of flu-like symptoms may precede neurological problems. Typically symptoms appear strongly in attacks (relapses) lasting several weeks, separated by periods of remission lasting several months. Nonetheless, as the disease progresses symptoms become increasingly present during the remission periods. The main symptoms of NMO are loss of vision and spinal cord function. Optic neuritis may manifest itself as visual impairment with decreased visual acuity, possibly with loss of colour vision. More than half of patients with relapsing NMO become blind in one or both eyes in five years. The effect on spinal cord function usually leads to muscle weakness, reduced sensation and even to loss of bladder and bowel control. A typical NMO sufferer may have acute and severe spastic weakness of the legs or even all four limbs with sensory signs and often accompanied by loss of bladder control. Death can result in some cases due to disruption of breathing during an attack. Pathology studies have revealed lesions in the optic nerve and spinal cord with evidence of inflammation and demyelination.
NMO, whilst displaying some symptoms which are similar to multiple sclerosis, (MS), such as recurrent attacks of neurological symptoms associated with disease activity in the optic nerve and spinal cord and leading to various disabilities with variable recovery, is in fact clearly distinct from MS clinically, radiologically, pathologically, and in terms of treatment approaches. This distinction is of great importance as management of NMO and prognosis of the disease are fundamentally different from MS.
In regard to clinical symptoms, the course of disease in the majority of both NMO and MS patients includes attacks (relapses) that typically last for weeks during which old symptoms may exacerbate and new ones appear. In comparison with MS the relapses in NMO are generally more frequent and more severe. In NMO these attacks alternate with stable periods during which the disabilities that appeared in the last relapse are maintained to some extent. In contrast, in early MS the symptoms that appeared during the preceding relapse(s) may resolve completely. In patients with later MS (and in a subset of cases called progressive MS) there is a slowly increasing severity of symptoms between relapses, and even a cessation of distinguishable relapse activity. This pattern is rare in NMO.
In regard to radiological findings, magnetic resonance imaging has shown that the spinal cord lesions in NMO patients, are longitudinally extensive involving three or more segments and are usually symmetrical (involving both sides of the cord to similar extents), whereas in MS the lesions in spinal cord are not as long and generally on one side of the cord only or predominantly. Lesions are infrequent in the brain at diagnosis and are generally not an important contributor to disability in NMO, whereas brain lesions are common and sometimes symptomatic in MS. Optic nerve lesions occur in both diseases.
In regard to involvement of elements of the immune system, in MS the attacks are believed to be mediated by infiltration of the immune system's T lymphocyte cells into the central nervous system along with activation of local microglial cells. Autoantibody involvement is suspected and the pertinent autoantigens are believed to be primarily myelin components. In NMO the disease is believed to be caused in part by serum autoantibodies called NMO-IgG. These antibodies target the protein aquaporin 4 (AQP-4) in the cell membrane of astrocytes. Aquaporin 4 acts as a channel for the transport of water across the cell membrane. It is found in the processes of the astrocytes that surround the blood-brain barrier, a system responsible for preventing substances in the blood from crossing into the brain. In NMO the blood-brain barrier is weakened, but at present it is not known how the NMO-IgG immune response results in demyelination. It is known, however, that the distribution of lesions in the NMO brain correlates with AQP-4 expression. T cell and B cell involvement is implied by the belief that azathioprine and rituximab are effective therapies, but eosinophils are the predominant cell type found in lesions upon pathological examination, in contrast to the predominant T cell pathology seen in MS.
Wingerchuk, D. M. et al in 2006 in Neurology, Vol. 66 no. 10 pp 1485-1489 proposed revised diagnostic criteria for defining NMO which required optic neuritis, myelitis and at least two of three supportive criteria, namely MRI evidence of continuous spinal cord lesion three or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis or NMO-IgG seropositivity. CNS involvement beyond the optic nerves and spinal cord is compatible with NMO.
There is currently no cure for NMO nor is there an FDA-approved or EMA-approved treatment for the disease due to the lack of adequate double-blind randomized placebo-controlled trials. However, symptoms can be treated. Attacks in NMO may be treated with short courses of intravenous corticosteroids such as methylprednisolone W. No controlled trials have established the effectiveness of treatments for the prevention of attacks.
Many clinicians consider that long-term immunosuppression is required to reduce the frequency and severity of attacks. The most commonly used immunosuppressive treatments are azathioprine plus prednisone, mycophenolate mofetil plus prednisone, rituximab, mitoxantrone, intravenous immunoglobulin and cyclophosphamide, with rituximab being considered the most promising treatment for relapsing NMO. Rituximab is a monoclonal antibody that targets clusters of differentiation (CD) 20 expressing cells, but its exact mode of action remains unclear. Furthermore, treatment with rituximab is known to cause side effects such as progressive multifocal leukoencephalopathy. Eculizumab is a recently tested experimental treatment in NMO.
There are a large number of potential therapies available for testing in autoimmune inflammatory diseases. However, it has not proven possible to predict which treatments, addressing which steps in the known pathology, will be successful in a given disease, for example in NMO. This is amply illustrated with two of the most widely used therapeutic strategies for disease course modification in relapsing MS. They are glatiramer acetate and one of the several marketed forms of the cytokine interferon beta. Both these treatments reduce relapse rate and lesion activity in the brain and spinal cord of MS patients. However, when interferon beta was tested in NMO, considered until then to be a disease similar to MS, it was unexpectedly and surprisingly found to have the opposite of the expected effect and to exacerbate NMO. Development of extensive brain lesions (Shimizu Y. et al., J. Neurol., 255; 305-307; (2008)) and clinical worsening (Uzawa A. et al., Eur. J. Neurol., 17; 672-676; (2010)) were reported in NMO patients treated with IFN-beta. Glatiramer acetate is believed to work by producing a beneficial change in T cell phenotype from the proinflammatory Th1 type to the regulatory Th2 type. Once again this well-proven treatment for MS has not been found to be effective and is not recommended for NMO (Awad A. and Stuve O., Current Neuropharmacology; 9; 417-428 (2011)).
Cladribine or 2-chloro-2′-deoxyadenosine has been used successfully in the oncology field with marked effects on lymphocytes. It has been found to be an effective treatment of hairy cell leukemia, chronic lymphocytic leukemia and some T cell malignancies. The addition of a chlorine atom at the 2 position of the adenine rings renders the molecule resistant to deamination by adenosine deaminase. Once taken up by cells in the body cladribine is converted enzymatically to cladribine triphosphate. Once formed inside the cell the unnatural chlorine-carrying cladribine derived nucleotides do not easily leave the cell and they can interact with cellular enzymes that normally work on the cell's natural deoxynucleotides. Two critical enzymes influencing the levels of cladribine nucleotides within a cell are cytidine kinase (CK) and nucleotidase (NT). It has been shown that levels of CK and NT enzyme expression vary between cell types and that lymphocytes have an especially high ratio of CK to NT expression. The combination of cladribine's resistance to adenosine deaminase and lymphocytes' high CK:NT ratio leads to the concentration and retention of cladribine nucleotides in human lymphocytes. This unique situation is responsible for cladribine's selectivity towards T and B lymphocytes when administered systemically.
The accumulation of cladribine nucleotides in lymphocytes has several known deleterious effects on the survival and function of lymphocyte cells. The result of these effects is death of both dividing and non-dividing lymphocytes. As a result it has been suggested that cladribine may be used for treating multiple sclerosis (see U.S. Pat. No. 5,506,214).
In addition to the foregoing effects of cladribine to cause death of lymphocytes by mechanisms dependent upon its intracellular phosphorylation, there are other means by which cladribine can affect immune system function. Induced cytokine production by human lymphocytes stimulated in culture by anti-CD3 and anti CD28 antibodies is decreased by cladribine treatment under conditions in which phosphorylation by CK is blocked and lymphocyte death does not occur (Laugel B. et al; J. Neuroimmunol; (2011); 240-241; 52-57).
Cladribine also binds with high affinity at a class of cell surface receptors called A2A (adenosine receptor class 2a). A2A receptors are found on T lymphocytes as well as other cell types in brain and the vasculature, and agents which bind A2A receptors have been shown to regulate overactive immune responses (Ohta A, Sitkovsky M. Nature 414: 916-20 (2001)).
Cladribine has also been reported to have been used to treat a single patient suffering from IgM associated inflammatory peripheral neuropathy that, unlike MS and NMO, is a non-relapsing, non-remitting disease. The drug was administered by intravenous infusion and levels of IgM antibodies were followed. (see Ghosh A. et al.; Neurology; 59; 1290-1291; (2002)). The patient had been on a deteriorating course for two years with increased symptoms and increased IgM levels, despite other treatments. After treatment with two courses of cladribine IgM levels declined slowly over a period of more than one year, at which time a symptomatic improvement was noted, and the improved symptoms and reduced IgM levels were both maintained for several years without further cladribine treatment.
Whilst cladribine has been used for treating other diseases including some leukemias and multiple sclerosis, and dosage regimens have been described (see EP 2263678) it could not have been predicted that cladribine would be effective in treating NMO. The inventors have unexpectedly found that cladribine may be beneficial in the treatment or amelioration of the autoimmune inflammatory disorder neuromyelitis optica. The inventors have further unexpectedly found that the sum of cladribine's effects on the immune system allows a short period of treatment (several weeks) to provide beneficial effects on the disease for a prolonged period of over 18 months without the need for retreatment at approximately yearly intervals.